Supporting Information
Discovery of a Peroxisome Proliferator Activated Receptor γ (PPARγ) γ) Modulator with Balanced PPARα α Activity for the Treatment of Type 2 Diabetes and Dyslipidemia Weiguo Liu, Kun Liu, Harold B. Wood, Margaret E. McCann, Thomas W. Doebber, Ching H. Chang, Taro E. Akiyama, Monica Einstein, Joel P. Berger and Peter T. Meinke Merck Research Laboratories, P. O. Box 2000, Rahway, New Jersey 07065
Table of Contents 1. Synthesis of optically active 2-bromoalkanecarboxylic acids: 2. Spectral and analysis data of compounds 15, 16, 17, 18 3. Results of elemental analysis of compounds 12c, 12d, 12g, 12h
S1
4. Chiral HPLC traces of selected compounds.
Synthesis of optically active 2-bromoalkanecarboxylic acids
(S)-2-Bromobutyric acid. A solution of (S)-2-aminobytyric acid (5 g, 48.5 mmol) and potassium bromide (25 g, 194 mmol) in dilute aqueous sulfuric acid (2.5 N) was cooled in an ice bath, and saturated aqueous solution of sodium nitrite (5 g, 72.8 mmol) was added drop wise through an addition funnel in a period of about 4 h maintaining the temperature of the solution below 5 oC. The mixture was then stirred at room temperature for 1 h, and extracted with ethyl acetate (2 x 40 mL). The organic extracts were combined, dried over anhydrous MgSO4, and concentrated to dryness to obtain 5.8 g (72% yield) of the title compound as an oil. 1H NMR (CDCl3, 500 MHz) δ: 1.07 (t, 3H), 2.14 (dd, 2H), 4.13 (t, 1H). The optical purity of the product was accessed after its conversion to 11d (see Experimental Section). (S)-2-Bromobutyric acid, methyl ester. To avoid racemization, the ester was prepared before immediate use. To a solution of (S)-2-bromobutyric acid (580 mg, 3.5 mmol) in benzene : methanol (4:1, 10 mL) was added drop wise a solution of (trimethylsilyl)diazomethane in hexane (2.0 M) until the bright yellow color generated in the solution no longer dissipate. The mixture was then concentrated under vacuum to dryness to obtain the title compound as an oil which was used immediately in the next step for displacement reactions (see Experimental Section)
S2
(S)-2-Bromovaleric acid. Prepared from L-norvaline following the same procedure as for (S)-2-bromobutyric acid. 1H NMR (CDCl3, 500 MHz) δ: 4.09 (t, 1H), 1.92 (m, 2H), 1.56 (m, 2H), 1.01 (t, 3H)
(S)-2-Bromo-4-methylvaleric acid. Prepared from L-valine following the same procedure as for (S)-2-bromobutyric acid. 1H NMR (CDCl3, 500 MHz) δ: 4.23 (d, 1H), 2.25 (m, 1H), 1.05 (d, 6H).
Spectral and analysis data of compounds 15, 16, 17, 18 (see experimental section for synthetic procedures)
Ethyl 2-(3-methylphenoxy)butyrate (15). 1H NMR (CDCl3, 500 MHz) δ: 7.27 (dd, 1H), 6.97 (d, 1H), 6.93 (s, 1H), 6.81 (d, 1H), 4.58 (t, 1H), 4.22 (q, 2H), 2.34 (s, 3H), 2.01 (m, 2H), 1.28 (t, 3H), 1.06 (t, 3H). Ethyl 2-methyl-2-(3-methylphenoxy)butyrate (16). 1H NMR (CDCl3, 500 MHz) δ: ) 7.25 (dd, 1H), 6.96 (d, 1H), 6.92 (s, 1H), 6.81 (d, 1H), 4.21 (q, 2H), 2.33 (s, 3H), 2.45 (s, 3H), 1.85 (m, 2H), 1.28 (t, 3H), 0.95 (t, 3H). Ethyl 2-methyl-2-(3-bromomethylphenoxy)butyrate (17). 1H NMR (CDCl3, 500 MHz) δ: 7.26 (t, 1H), 7.01 (d, 1H), 6.95 (s, 1H), 6.82 (d, 1H), 4.46 (s, 2H), 4.25 (q, 2H), 2.44 (s, 3H),1.86 (m, 2H), 1.29 (t, 3H), 0.95 (t, 3H).
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Results of elemental analysis of compound 12c, 12d, 12g, 12h. compound
formula
calculated
found
C%
H%
C%
H%
12c
C28H23ClF3NO5
61.60
4.25
61.72
4.25
12d
C28H23ClF3NO5
61.60
4.25
61.67
4.28
12g
C29H25ClF3NO5
62.20
4.50
62.25
4.45
12h
C29H25ClF3NO5
62.20
4.50
62.31
4.48
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Chiral HPLC traces of selected compounds:
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